Urea and thiourea derivatives



Patented Aug. 26,1941

UNITED STATE 2,254,136 UREA AND TH IOI JREA DERIVATIVES Johannes S.Buck,

Bronxville, and Edwin J.

de Beer, Tuckahoe, N. Y.

Serial No.

4 Claims.

closed.

Although the novel features which are believed to be characteristic ofthis invention will be pointed pended hereto, the invention will bebetter understood by referring to the following description in which aspecific embodiment thereof has been set forth for purposes ofillustration.

In accordance with the present invention we have found that ureaderivatives of the following type possess valuable hypnotic propertiesand are suitable for use as general or local anesthetics.

the R represents an alkyl for example as methyl, allyl, etc. Rrepresents hydrogen or an alkyl or alkenyl group such as' the examplesspecified above. R" represents hydrogen or an alkyl or alkenyl groupsuch as the examples specified above, which may or may not be the samegroup as R. R' represents an alkyl group containing more than one carbonatom such ethyl, propyl, isopropyl, etc., which may be in the ortho,meta or para position. One or more of the remaining four hydrogen atomsof the benzene nucleus may also be replaced by various substituents toform derivatives of the above.

The above compounds may be prepared by various methods suited to theproduction of urea In the above examples or alkenyl group such ethyl,propyl, isopropyl,

' and thiourea derivatives such for example as,

among others:

out more particularly in the claims ap- No Drawing. Application May 10,1939,

Urea derivatives (a) The action of nitrourea on the appropriatealkylarylamine.

(b) The action of ammonium or metallic cyanates or isocyanates on theappropriate alkylarylamine salt.

(0) The action of the chlorides of carbamic acids on the appropriatealkylarylamine or on ammonia or an aliphatic amine.

(d) The interaction of urea or substituted ureas with the appropriatesecondary amine.

(e) The action of alkyl cyanates or isocyanates on the appropriatealkylarylamine.

(f) The action of hydrolytic agents on the appropriate ureide.

(g) Desulfurisation of the corresponding thiourea derivative, forexample, by means of alcoholic silver nitrate.

(h) The alkylation or responding urea derivative with H in the place ofR.

Thiourea derivatives The action of ammonium or metallic thiocyanates orisothiocyanates on the appropriate alkylarylamine salt.

(1) The action of thiocyanates or isothiocyanates on the appropriateamine.

(1c) Heatiiig the amine salts of dithiocarbamic ac s. (1) Heatingaminothiocyanates or aminoisothiocyanates.

(1n) Addition of hydrogen sulfide to the appropriate disubstitutedcyanamide.

(n) Th action of ammonia or amines on the appropriate dithiourethane.

Specific examples are as follows:

Example 1 C H -N-CO-NH:

CzH-s Uns.-ethyl-o-ethylphenylurea may be made as follows:

40.0 grams ethyl-o-ethylaniline and cc. per cent ethyl alcohol are mixedand warmed to about 60 C. 39.3 grams nitrourea is added in portions,with stirring, the temperature bein alkylenation of the corkept at about60-70 C. during the addition. Care should be taken that the reactionproceeds without delay and that gas is evolved continuously. After thenitrourea has all been added, the mixture is heated for one hour on thesteam bath, filtered and about three-fourths of the alcohol evaporatedoil. A volume of benzene, ap-

The product forms white or colorless crystals, I

melting at 70-'7l melting at about 75 C. is occasionally otbained,particularly when isopropyl ether is the solvent.

Example 2 (CHOaCH-N-C O-NH:

02H! Uns.-isopropyl-p-ethylphenyi urea may be made as follows:

11.2 grams isopropyl-p-ethylaniline and 50 cc. 95 per cent ethylalcohol, together with 8.5 grams of nitrourea, are placed in a flask andcautiously heated on the water bath. A brisk evolution of gas takesplace. When the reaction is ended, approximately two-thirds of thealcohol is evaporated off and water added to incipient precipitation. Onstanding in a cold place, and particularly after seeding, a crop oftransparent crystals separates. After recrystallization from a suitablesolvent (e. g. benzene-hexane mixture) the compound forms white 0rcolorless crystals melting at about 104 C.

Uns.-ethy1-p-eth;l%lianyl thiourea may be made as follows:

10.0 grams ethyl-p-ethylaniline are dissolved in a mixture of 7 cc.water and 7 cc. concentrated hydrochloric acid. To this is added asolution of 5.5 grams ammonium thiocyanate in 7 cc. water.

C. A second modification,

A colorless oil separates. The whole is heated in an evaporating dish onthe steam bath for about 6 hours and the upper layer then decanted. Bothlayers are then heated in separate dishes for approximately 6 hoursmore. By this time the water should be completely evaporated. Theresidues are extracted with warm benzene and the extract filtered andconcentrated to about 20 cc. After adding a little hexane (about 5 cc.)and seeding, the product crystallizes out on standing. The product isfiltered oil. and recrystallized from a suitable solvent, e. g., ethylacetate-hexane mixture, until sufilciently pure. The thiourea formswhite or colorless crystals melting at l02-103 C.

The above are specific examples only of the type of compounds describedabove which have been found to possess hypnotic properties. It is to beunderstood that the other compounds may be prepared in a similar manneror in other ways as will be apparent to a person skilled in the art.These compounds may also form the basis for other preparations such asdouble compounds, molecular compounds, mixtures, salts, etc. Thecompounds are also of general application to other uses. The inventionis only to be restricted by the following claims.

What we claim is:

1. A compound of the general formula in which R represents a member ofthe group consisting of the alkyl and alkenyl radicals having less thaneight carbon atoms, A represents a member of the group consisting of 0and S, R represents a member of the group consisting of hydrogen and thealkyl and alkenyl radicals of less than eight carbon atoms, R"represents a member of the group consisting of hydrogen and the alkyland alkenyl radicals of less than eight carbon atoms, and R represents amember of the group consisting of an alkyl radical having more than oneand less than eight carbon atoms and a plurality of alkyl radicals eachhaving less than eight carbon atoms.

2. A new composition of matter consisting of uns.-ethyl-o-ethylphenylurea.

3. A new composition of matter consisting ofuns.-isopropyl-p-ethylphenyl urea.

4. A new composition of matter consisting of uns.-ethyl-p-ethylphenylthiourea.

JOHANNES S. BUCK. EDWIN J. an BEER.

